Deafness, Congenital, with Inner Ear Agenesis, Microtia, and Microdontia via the FGF3 Gene

Congenital deafness with inner ear agenesis, microtia, and microdontia, also known as deafness with labyrinthine aplasia, microtia, and microdontia (LAMM) or Michel aplasia, microdontia, and malformation of the inner ear, is characterized by profound congenital sensorineural hearing loss combined with slightly smaller ears (type I microtia) and smaller teeth (microdontia) that are often widely spaced apart (Alsmadi et al. 2009). The ears of LAMM patients generally show shortened auricles, particularly at the crura of the antihelix. Computed tomography imaging of the temporal bones of LAMM patients often show complete bilateral absence of structures of the inner ear, which include the cochlea, vestibule, and semicircular canals. However, the middle ear of LAMM patients remains intact. Although physical examination of individuals with LAMM generates normal results, they are generally delayed in motor development during infancy, mainly due to impaired balance that is caused by the absence of structures of the inner ear. Despite their hearing impairment, LAMM patients have normal cognitive abilities and do not experience difficulties in writing or reading. Certain patients with LAMM may present less prominent dental as well as external ear features, yet their inner ear often present structural abnormalities (Riazuddin et al. 2011). The symptoms of small ears and teeth are also observed in patients with lacrimoauriculodentodigital (LADD) syndrome (Mathrawala and Hegde 2011).

Congenital deafness with inner ear agenesis, microtia, and microdontia is an autosomal recessive hearing disorder that is caused by pathogenic sequence variants in the fibroblast growth factor 3 (FGF3) gene, which is located in chromosome 11q13.3 (Casey et al. 1986). The FGF3 gene consists of 3 coding exons that encode a 239-amino acid oncoprotein, which is mainly expressed in the rhombencephalon during fetal development when inner ear induction occurs, acting as a signal for the formation of the otic vesicle (Frenz et al. 2010). Disease-causing sequence variants in the FGF3 gene have also been implicated in three other disorders, namely, otodental syndrome (characterized by grossly enlarged molar teeth and high-frequency sensorineural hearing loss), craniosynostosis (a birth defect that involves premature fusion of the skull bones of an infant, thereby changing the growth pattern of the skull), and odontoma-dysphagia syndrome (presents with grossly enlarged, clustered teeth, slight facial abnormalities, and difficulty to swallow) (Gregory-Evans et al. 2007; Grillo et al. 2014). To date, a total of about 20 pathogenic FGF3 sequence variants have been reported, which include 10 missense/nonsense and 4 small deletions that cause LAMM, 3 gross deletions that cause otodental syndrome, and 2 gross insertions that cause craniosynostosis, and 1 gross insertion that causes odontoma-dysphagia (Human Gene Mutation Database).

No large-scale studies have been conducted on sequence variants in the FGF3 gene, thus its clinical sensitivity is unclear. Of the seven available reports on pathogenic sequence variants in the FGF3 gene, two were case reports (Dill et al. 2011; Singh et al. 2014), whereas five were small-scale family studies consisting of 1 to 3 families, with each family having 2 to 21 affected members (Tekin et al. 2007; Alsmadi et al. 2009; Riazuddin et al. 2011; Sensi et al. 2011; Schaefer et al. 2014).

This test provides full coverage of all coding exons of the FGF3 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).